Our current understanding of cutaneous innate immunity states that the skin initially protects against infection by establishing physical and chemical barriers to microbes. These include the stratum corneum, antimicrobial peptides, reactive oxygen species, hostile pH and antimicrobial free fatty acids. Despite a potent constitutive immune defense system however, human skin permits the survival of a unique microbial population on the surface called the microbiome. Although much recent effort has been applied to defining the components of the microbiome on human skin, its function is unknown. We hypothesize that the microbiome is an important part of the immune shield and that interaction of the microbiome with keratinocytes is critical to this process. Our preliminary data show for the first time that the most commonly cultured bacterium of the human skin microbiome, Staphylococcus epidermidis, can work in three ways to aid skin immune defense. 1. S. epidermidis produces antimicrobial peptides that kill pathogens such as S. aureus and Group A Streptococcus, 2. It releases a factor that enhances endogenous production of antimicrobial peptides by keratinocytes, and 3. It triggers pattern recognition receptors in such a way that it prevents keratinocytes from triggering inflammation under certain conditions. Based on these observations our main hypothesis is that Staphylococcus epidermidis is important to the cutaneous immune defense strategy. Our specific aims are: Aim 1. Understand how the antimicrobial peptide(s) produced by S. epidermidis (SE) act to selectively kill skin pathogens. Aim 2. Discover what molecules produced by SE induce AMP expression by keratinocytes. Aim 3. Define the molecular mechanisms by which SE inhibits inflammatory cytokine production by keratinocytes. Successful completion of these aims will provide new understanding of skin immunity and move towards developing novel therapeutic approaches to improving treatment of skin disease.